A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

Tumor Location Is an Independent Prognostic Factor in Completely Resected Pathological Stage I Non-Small Cell Lung Cancer: A Multicenter Retrospective Study.

Previous studies suggested that the location of the primary tumor in non-small cell lung cancer (NSCLC) is associated with clinical features and prognosis, but results are conflicting. The purpose of this study was to explore tumor location as an independent risk factor of survival for patients with completely resected pathological stage I NSCLC. This was a multicenter retrospective study conducted in Taiwan. Included patients were diagnosed with stage I NSCLC and had undergone primary tumor resection. Variables including tumor location, pathological stage, histological differentiation, and International Association for the Study of Lung Cancer (IASLC) grade were evaluated for predictive ability for disease-free survival (DFS) and overall survival (OS). A total of 208 patients were included, with 123 (59.1%) patients having a primary tumor in the upper and middle lobes. The median duration of follow-up for survivors was 60.5 months. Compared to patients with IASLC Grade 3 disease, patients with Grade 1 disease had significantly longer DFS. Tumor location and IASLC grade were independent predictors for OS in multivariate analysis. Specifically, patients with NSCLC in the lower lobe and patients who are histologically classified as IASLC Grade 3 may have poorer prognosis and require greater attention to improve outcomes.

Interprofessional Differences in Multidimensional Self-Efficacy Associated With Professional Performance in Nephrology During Case-Based Learning.

Introduction: Postgraduate medical education assumes rising importance in the rapidly advancing field of medicine. Case-based learning (CBL), a learner-centered pedagogy employing clinical cases to improve decision-making, is widely embraced in postgraduate medical education, including nephrology. Studies suggest that learning self-efficacy (SE) was closely associated with learning motivation and academic performance; however, very few studies examined this association in postgraduate nephrology education. None evaluated whether there were interprofessional differences concerning such association. Methods: In 2022, we prospectively enrolled physicians and nurses participating in chronic kidney disease (CKD) care from institutions around Taiwan. They completed the Professional Medical Learning Self-efficacy (PMLS) questionnaire after attending >1 CBL session involving CKD care. We undertook confirmatory factor analysis (CFA), followed by structural equation modeling (SEM) to evaluate associations between 5 dimensions of learning SE (conceptual understanding [CU], higher-order cognitive skills [HC], practical work [PW], everyday application [EA], and medical science communication [MSC]) and their professional SE in nephrology according to participants' medical professions. Results: A total of 513 healthcare providers were surveyed. The convergent and construct validity of our questionnaire were satisfied after analyses. We found that better perceived professional performance in the form of higher professional SE in nephrology was significantly associated with all 5 dimensions of learning SE among physicians and nurses. Only CU and PW were significantly associated with physicians' professional performance; whereas among nurses, only HC and MSC were significantly associated. Conclusion: We showed that learning SE was an important determinant of nephrology professional performance. Different medical professions posed influences on major SE dimensions.

Progress of Clinical Studies Targeting Claudin18.2 for the Treatment of Gastric Cancer.

Claudin18.2 is a tight junction protein, highly selective, generally expressed only in normal gastric mucosal epithelial cells, which can effectively maintain the polarity of epithelial and endothelial cells, thus effectively regulating the permeability and conductance of the paracellular pathway. Abnormal expression of Claudin18.2 can occur in various primary malignant tumors, especially gastrointestinal tumors, and even in metastatic foci. It regulates its expression by activating the aPKC/MAPK/AP-1 pathway, and therefore, the Claudin18.2 protein is a pan-cancer target expressed in primary and metastatic lesions in human cancer types. Zolbetuximab (IMAB362), an antibody specific for Claudin18.2, has been successfully tested in a phase III clinical trial, and the results of the study showed that combining Zolbetuximab with chemotherapy notably extends patients' survival and is expected to be a potential first-line treatment for patients with Claudin18.2(+)/HER-2(-) gastric cancer. Here, we systematically describe the biological properties and oncogenic effects of Claudin18.2, centering on its clinical-pathological aspects and the progress of drug studies in gastric cancer, which can help to further explore its clinical value.

Photochemical Strategies toward Precision Targeting against Multidrug-Resistant Bacterial Infections.

Infectious diseases pose a serious threat and a substantial economic burden on global human and public health security, especially with the frequent emergence of multidrug-resistant (MDR) bacteria in clinical settings. In response to this urgent need, various photobased anti-infectious therapies have been reported lately. This Review explores and discusses several photochemical targeted antibacterial therapeutic strategies for addressing bacterial infections regardless of their antibiotic susceptibility. In contrast to conventional photobased therapies, these approaches facilitate precise targeting of pathogenic bacteria and/or infectious microenvironments, effectively minimizing toxicity to mammalian cells and surrounding healthy tissues. The highlighted therapies include photodynamic therapy, photocatalytic therapy, photothermal therapy, endogenous pigments-based photobleaching therapy, and polyphenols-based photo-oxidation therapy. This comprehensive exploration aims to offer updated information to facilitate the development of effective, convenient, safe, and alternative strategies to counter the growing threat of MDR bacteria in the future.

Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice.

Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg· kg-1 ·d-1, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 µM) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg ·kg-1 ·d-1, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.

Target organ damage in untreated hypertensive patients with primary aldosteronism.

An increased risk of target organ damage (TOD) has been reported in patients with primary aldosteronism (PA). However, there is relatively little related research on the correlation between the degree of TOD and those with and without PA in newly diagnosed hypertensive patients. The aim of this study was to assess the association between PA and TOD among patients with newly diagnosed hypertension. Newly diagnosed hypertensive patients were consecutively recruited from January 2015 to June 2020 at the University of Hong Kong-Shenzhen Hospital. Patients were stratified into those with and without PA. Data for left ventricular mass index (LVMI), carotid intima-media thickness (CIMT) and plaque, and microalbuminuria were systematically collected. A total of 1044 patients with newly diagnosed hypertension were recruited, 57 (5.5%) of whom were diagnosed with PA. Patients with PA had lower blood pressure, serum lipids, body mass index, and plasma renin activity and a higher incidence of hypokalemia than those without PA. In contrast, the prevalence of left ventricular hypertrophy, increased CIMT, and microalbuminuria was higher in patients with PA than in those without PA. Multivariable regression analysis demonstrated that PA was independently associated with increased LVMI, CIMT and microalbuminuria. Among patients with newly diagnosed hypertension, those with PA had more severe TOD, including a higher LVMI, CIMT and microalbuminuria, than those without PA. These findings emphasize the need for screening TOD in newly diagnosed hypertension due to underlying PA.

Polysaccharides extracted from larvae of Lucilia sericata ameliorated ulcerative colitis by regulating the intestinal barrier and gut microbiota.

Pest management technology has been a promising bioconversion method for waste resource utilization. Unlike many pests that consume waste, the larvae of Lucilia sericata, also known as maggots, have many outstanding advantages as following: with their strong adaption to environment and not easily infected and exhibiting a medicinal nutritional value. Herein, the potential efficacies of maggot polysaccharides (MP), as well as their underlying mechanisms, were explored in Dextran sulfate sodium (DSS)-induced colitis mice and TNF-α-elicited Caco-2 cells. We extracted two bioactive polysaccharides from maggots, MP-80 and MP-L, whose molecular weights were 4.25 × 103 and 2.28 × 103 g/mol, respectively. MP-80 and MP-L contained nine sugar residues: 1,4-α-Arap, 1,3-ß-Galp, 1,4,6-ß-Galp, 1,6-α-Glcp, 1-α-Glcp, 1,4-ß-Glcp, 1-ß-Xylp, 1,2-α-Manp, and 1-ß-Manp. We demonstrated that MP-80 and MP-L significantly ameliorated DSS-induced symptoms and histopathological damage. Immuno-analysis revealed that compared with MP-L, MP-80 could better restore intestinal barrier and reduced inflammation by suppressing NLRP3/NF-κB pathways, which might be attributed to its enriched galactose fraction. Moreover, 16S rRNA sequencing revealed that MP-80 and MP-L both improved the dysbiosis and diversity of gut microbiota and acted on multiple microbial functions. Our study sheds new light on the possibility of using maggot polysaccharides as an alternative therapy for colitis.

Translation and adaptation of Shared Care Instrument-Revised for the older adults and their caregivers in Taiwan.

BACKGROUND: The aging population in Taiwan has resulted in an increase in the dependent population and the care load on caregivers. Shared care is an interpersonal process in which support is "traded" to "handle" chronic illnesses by home-care patients and family caregivers. The scale of shared care has received little attention in the Taiwanese cultural context. Thus, this study examined the reliability and validity of the Taiwanese versions of Shared Care Instrument-Revised (SCI-R). METHODS: The content validity, construct validity, and discriminant validity were used to test the validity of the translated questionnaires. The Cronbach's α was used to examine reliability. A total of 500 older adults and their caregivers were recruited from three counties in Taiwan. RESULTS: The reliability and validity of the Chinese version of the scale were within the acceptable range. The Cronbach's α was between 0.838 and 0.95. However, the scale's reliability was higher than that of the original version. This might be because of the inclusion of participants with less severe diseases than the participants in the original study, high social expectations in the Chinese traditional culture, and a large number of similar items. Future research should simplify the items and consider adopting diverse participant selection criteria. CONCLUSIONS: The results of this study can be used to understand shared care in Taiwan.

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans.

Twelve new alkaloids, scolopenolines A-L (1-7, 9-11, 13, 14), along with six known analogues, were isolated from Scolopendra subspinipes mutilans, identified by analysis of spectroscopic data and quantum chemical and computational methods. Scolopenoline A (1), a unique guanidyl-containing C14 quinoline alkaloid, features a 6/6/5 ring backbone. Scolopenoline B (2) is a novel sulfonyl-containing heterodimer comprising quinoline and tyramine moieties. Scolopenoline G (7) presents a rare C12 quinoline skeleton with a 6/6/5 ring system. Alkaloids 1, 8, 10, and 15-18 display anti-inflammatory activity, while 10 and 16-18 also exhibit anti-renal-fibrosis activity. Drug affinity responsive target stability and RNA-interference assays show that Lamp2 might be a potentially important target protein of 16 for anti-renal-fibrosis activity.

Overexpressed KCNK1 regulates potassium channels affecting molecular mechanisms and biological pathways in bladder cancer.

BACKGROUND: This study aimed to explore the expression, molecular mechanism and its biological function of potassium two pore domain channel subfamily K member 1 (KCNK1) in bladder cancer (BC). METHODS: We integrated large numbers of external samples (n = 1486) to assess KCNK1 mRNA expression levels and collected in-house samples (n = 245) for immunohistochemistry (IHC) experiments to validate at the KCNK1 protein level. Single-cell RNA sequencing (scRNA-seq) analysis was performed to further assess KCNK1 expression and cellular communication. The transcriptional regulatory mechanisms of KCNK1 expression were explored by ChIP-seq, ATAC-seq and ChIA-PET data. Highly expressed co-expressed genes (HECEGs) of KCNK1 were used to explore potential signalling pathways. Furthermore, the immunoassay, clinical significance and molecular docking of KCNK1 were calculated. RESULTS: KCNK1 mRNA was significantly overexpressed in BC (SMD = 0.58, 95% CI [0.05; 1.11]), validated at the protein level (p < 0.0001). Upregulated KCNK1 mRNA exhibited highly distinguishing ability between BC and control samples (AUC = 0.82 [0.78-0.85]). Further, scRNA-seq analysis revealed that KCNK1 expression was predominantly clustered in BC epithelial cells and tended to increase with cellular differentiation. BC epithelial cells were involved in cellular communication mainly through the MK signalling pathway. Secondly, the KCNK1 transcription start site (TSS) showed promoter-enhancer interactions in three-dimensional space, while being transcriptionally regulated by GRHL2 and FOXA1. Most of the KCNK1 HECEGs were enriched in cell cycle-related signalling pathways. KCNK1 was mainly involved in cellular metabolism-related pathways and regulated cell membrane potassium channel activity. KCNK1 expression was associated with the level of infiltration of various immune cells. Immunotherapy and chemotherapy (docetaxel, paclitaxel and vinblastine) were more effective in BC patients in the high KCNK1 expression group. KCNK1 expression correlated with age, pathology grade and pathologic_M in BC patients. CONCLUSIONS: KCNK1 was significantly overexpressed in BC. A complex and sophisticated three-dimensional spatial transcriptional regulatory network existed in the KCNK1 TSS and promoted the upregulated of KCNK1 expression. The high expression of KCNK1 might be involved in the cell cycle, cellular metabolism, and tumour microenvironment through the regulation of potassium channels, and ultimately contributed to the deterioration of BC.

Overexpression of SYNGAP1 suppresses the proliferation of rectal adenocarcinoma via Wnt/ß-Catenin signaling pathway.

Rectal adenocarcinoma (READ) is a common malignant tumor of the digestive tract. Growing studies have confirmed Ras GTPase-activating proteins are involved in the progression of several tumors. This study aimed to explore the expression and function of Ras GTPase-activating proteins in READ. In this study, we analyzed RNA sequencing data from 165 patients with READ and 789 normal tissue samples, identifying 5603 differentially expressed genes (DEGs), including 2937 upregulated genes and 2666 downregulated genes. Moreover, we also identified two dysregulated genes, RASA4 and SYNGAP1, among six Ras GTPase-activating proteins. High NF1 expression was associated with longer overall survival, while high SYNGAP1 expression showed a trend towards extended overall survival. Further analysis revealed the mutation frequency and copy number variations of Ras GTPase-activating proteins in various cancer samples. Additionally, DNA methylation analysis demonstrated a negative correlation between DNA methylation of Ras GTPase-activating proteins and their expression. Moreover, among Ras GTPase-activating proteins, we focused on SYNGAP1, and experimental validation confirmed that the overexpression of SYNGAP1 in READ significantly suppressed READ cell proliferation and increased apoptosis via regulating the Wnt/ß-Catenin signaling pathway. These findings underscored the potential significance of SYNGAP1 in READ and provide new insights for further research and treatment.

Investigation of the correlation between platelet antibodies and peripheral blood cytopenia in patients with hepatocellular carcinoma.

The primary triggers that stimulate the body to generate platelet antibodies via immune mechanisms encompass events such as pregnancy, transplantation, and blood transfusion. Interestingly, our findings revealed that a subset of male patients with hepatocellular carcinoma (HCC), despite having no history of transplantation or blood transfusion, has shown positive results in platelet antibody screenings. This hints at the possibility that certain factors, potentially related to the tumor itself or its treatment, may affect antibody production. To delve the causes we initiated this study. We employed a case-control study approach to analyze potential influential factors leading to the positive results via univariate and multivariate regression analysis. We utilized Kendall's tau-b correlation to examine the relationship between the strength of platelet antibodies and peripheral blood cytopenia. Antitumor medication emerged as an independent risk factor for positive results in HCC patients, and the strength of platelet antibodies positively correlated with the severity of anemia and thrombocytopenia. Without history of blood transfusion, transplantation, pregnancy, those HCC patients underwent recent tumor medication therapy are experiencing peripheral erythrocytopenia or thrombocytopenia, for them platelet antibody screenings holds potential clinical value for prevention and treatment of complications like drug-immune-related anemia and/or bleeding.

First Report of Phyllosticta capitalensis Causing Leaf spot in Hymenocallis littoralis in China.

Hymenocallis littoralis (Jacq.) Salisb. is a common ornamental plant in China. In November 2021, leaf spots were observed on H. littoralis in a public garden in Zhanjiang, Guangdong Province, China (21°17'25″N, 110°18'12″E). Disease incidence was around 60% (n = 100 investigated plants from about 1 ha). Leaf symptoms were round spots with collapse centers, surrounded by yellow halos. Ten symptomatic leaves from 10 plants were sampled. The margins of the samples were cut into 2 mm × 2 mm pieces. The surfaces were disinfected with 75% ethanol for 30 s and 2% sodium hypochlorite for 60 s. Thereafter, the samples were rinsed thrice in sterile water, placed on PDA, and incubated at 28 °C in dark. Pure cultures were obtained by transferring hyphal tips to new PDA plates. Twenty pure cultures were obtained. Single-spore isolation method (Liu et al. 2021) was used to recover the cultures of three isolates (HPC-1, HPC-2, and HPC-3). Colonies of the isolates were dark green with a granular surface, and irregular white (later turning black) edge. Pycnidia were black, globose and 96 -140 µm in diameter. Conidia were single-celled, oval, 7.5 to 13.5 × 4.0 to 7.5 µm (n = 40), with a single apical appendage. Morphological characteristics of the isolates were consistent with the description of Phyllosticta capitalensis (Wikee et al. 2013). Molecular identification was performed using PCR method with MightyAmp DNA Polymerase (Takara-Bio, Dalian, China) (Lu et al. 2012). The internal transcribed spacer (ITS) region, translation elongation factor (TEF1), actin (ACT), and glyceradehyde-3-phosphate dehydrogenase (GAPDH) were amplified using primers ITS1/ITS4, EF1-728F/EF1-986R (Druzhinina et al. 2005), ACT-512F/ACT-783R, and Gpd1-LM/Gpd2-LM (Wikee et al. 2013), respectively. Sequences were deposited in GenBank with accession numbers OM654570 - OM654572 for ITS, OM831376 - OM831378 for tef1-α, OM831346 - OM831348 for ACT, and OM831364 - OM831366 for GAPDH. BLASTn analysis showed that these sequences were 99 to 100% similarity with those of P. capitalensis (ITS, FJ538339; TEF1, FJ538397; ACT, FJ538455; and GAPDH, JF343723). Besides, a phylogenetic tree was generated on the basis of the concatenated data from the sequences of ITS, TEF1, ACT, and GAPDH that nested within the clade containing P. capitalensis (CBS 117118, CPC20510,CPC20267, and CPC18848). From the combination of the morphological and molecular characteristics, the isolates were determined to be P. capitalensis. Pathogenicity testing was performed in a greenhouse with 80% relative humidity at 25 to 30°C. Ten healthy plants of H. littoralis (2 month old with 4 leaves) were grown in pots with one plant in each pot. Three leaves on one plant per isolate were inoculated with three mycelial plugs obtained from 7-day cultures, totaling five plants. Five plants treated with PDA plugs served as the controls. Wet cotton balls were fixed on the leaves with transparent tape for five days to keep it from drying out. The test was conducted three times. After 15 days, similar symptoms were observed in the inoculated leaves as in the garden, whereas control leaves remained asymptomatic and P. capitalensis was successfully re-isolated from the inoculated leaves. Previously, P. capitalensis has been reported to cause leaf spot disease of various host plants around the world (Wikee et al. 2013). However, to our knowledge, this is the first report of leaf spot caused by P. capitalensis on H. littoralis in China. This study provides an important reference for the control of the disease.

Selective orexin 2 receptor blockade alleviates cognitive impairments and the pathological progression of Alzheimer's disease in 3xTg-AD mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting and ELISA were used to detect Aß deposition, tau phosphorylation and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Glycated Hemoglobin Variability Is Associated With Adverse Outcomes in Patients With Heart Failure Irrespective of Diabetic Status.

BACKGROUND: The effect of glycated hemoglobin (HbA1c) variability on adverse outcomes in patients with heart failure (HF) is unclear. We aim to investigate the predictive value of HbA1c variability on the risks of all-cause death and HF rehospitalization in patients with HF irrespective of their diabetic status. METHODS AND RESULTS: Using a previously validated territory-wide clinical data registry, HbA1c variability was assessed by average successive variability (ASV) or SD of all HbA1c measurements after HF diagnosis. Multivariable Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and its corresponding 95% CI. A total of 65 950 patients with HF were included in the study. Over a median follow-up of 6.7 (interquartile range, 4.0-10.6) years, 34 508 patients died and 52 446 required HF rehospitalization. Every unit increment of variability in HbA1c was significantly associated with higher HF rehospitalization (HR ASV, 1.20 [95% CI, 1.18-1.23]) and all-cause death (HR ASV, 1.50 [95% CI, 1.47-1.53]). Diabetes significantly modified the association between HbA1c variability and outcomes (Pinteraction<0.001). HbA1c variability in patients with HF without diabetes conferred a higher risk of rehospitalization (HR ASV, 1.92 [95% CI, 1.70-2.17] versus HR ASV, 1.19 [95% CI, 1.17-1.21]), and all-cause death (HR ASV, 3.90 [95% CI, 3.31-4.61] versus HR ASV, 1.47 [95% CI, 1.43-1.50] compared with patients with diabetes). CONCLUSIONS: HbA1c variability is significantly associated with greater risk of rehospitalization and all-cause death in patients with HF, irrespective of their diabetic status. These observations were more pronounced in patients with HF without diabetes.

Rapamycin improves the survival of epilepsy model cells by blocking phosphorylation of mTOR base on computer simulations and cellular experiments.

PURPOSE: Epilepsy is a chronic brain dysfunction characterized by recurrent epileptic seizures. Rapamycin is a naturally occurring macrolide from Streptomyces hygroscopicus, and rapamycin may provide a protective effect on the nervous system by affecting mTOR. Therefore, we investigated the pharmacologic mechanism of rapamycin treating epilepsy through bioinformatics analysis, cellular experiments and supercomputer simulation. METHODS: Bioinformatics analysis was used to analyze targets of rapamycin treating epilepsy. We established epilepsy cell model by HT22 cells. RT-qPCR, WB and IF were used to verify the effects of rapamycin on mTOR at gene level and protein level. Computer simulations were used to model and evaluate the stability of rapamycin binding to mTOR protein. RESULTS: Bioinformatics indicated mTOR played an essential role in signaling pathways of cell growth and cell metabolism. Cellular experiments showed that rapamycin could promote cell survival, and rapamycin did not have an effect on mRNA expression of mTOR. However, rapamycin was able to significantly inhibit the phosphorylation of mTOR at protein level. Computer simulations indicated that rapamycin was involved in the treatment of epilepsy through regulating phosphorylation of mTOR at protein level. CONCLUSION: We found that rapamycin was capable of promoting the survival of epilepsy cells by inhibiting the phosphorylation of mTOR at protein level, and rapamycin did not have an effect on mRNA expression of mTOR. In addition to the traditional study that rapamycin affects mTORC1 complex by acting on FKBP12, this study found rapamycin could also directly block the phosphorylation of mTOR, therefore affecting the assembly of mTORC1 complex and mTOR signaling pathway.

[Two new benzyl-benzoate glucosides from Plumeria rubra].

The components with hypoglycemic activity in Plumeria rubra were isolated and purified by various column chromatography techniques and activity tracing methods. The physical and chemical properties of all the purified monomer compounds were characterized and analyzed, and a total of six compounds were isolated and identified, including 6″-acetyl-6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside(1), 6-acetyl-6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-glucoside(2), 2-hydroxy-6-methoxy-benzyl-benzoate-2-O-ß-D-glucoside(3), 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside(4), 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-glucoside(5), and 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-xyloside(6). Compounds 1 and 2 were new compounds, and compounds 3-6 were isolated from Plumeria for the first time. The α-glucosidase inhibitory activity of six identified compounds was tested. The results show that compounds 1-6 show certain inhibitory activity with an IC_(50) value ranging from 8.2 to 33.5 µmol·L~(-1).

Role of Peritoneal Equilibration Test in Assessing Folate Transport During Peritoneal Dialysis.

OBJECTIVES: Low plasma folate levels have been reported in patients undergoing hemodialysis and peritoneal dialysis (PD) in clinical studies. However, folate transport has never been mentioned as a factor contributing to low plasma folate levels in patients undergoing PD. The peritoneal equilibrium test (PET) assesses the plasma creatinine level and glucose transport abilities. This study aimed to evaluate the association between plasma folate levels and folate transport during PD based on PET grades. METHODS: This study recruited 50 patients who underwent PD for ≥3 months and were categorized according to PET grades. Data regarding plasma folate levels and dialysate folate were collected. The primary outcomes were the relationship between the PET grade and plasma folate level and between the PET grade and dialysate-to-plasma folate concentration ratio (D/P folate). Furthermore, the difference in the plasma folate level and D/P folate between men and women was assessed. RESULTS: The plasma folate level and the D/P folate significantly differed among the 4 PET groups (both P < .001). PET grade was significantly negatively correlated with plasma folate levels (r = -0.56, P < .001) and positively correlated with D/P folate (r = 0.686, P < .001). In subgroup analysis, neither the plasma folate level nor the D/P folate significantly differed between men and women. CONCLUSIONS: Our study provides clinical evidence that the PET grade is associated with the plasma folate level and D/P folate, regardless of sex. Larger cohort studies are warranted to assess the importance of folate supplementation during PD based on PET grades.